Abstract
Malignant hyperthermia (MH) susceptibility has been attributed to a leaky sarcoplasmic reticulum (SR) caused by missense mutations in RYR1 or CACNA1S, and the MH crisis has been attributed solely to massive self-sustaining release of Ca2+ from SR stores elicited by triggering agents. Here, we show in muscle cells from MH-RyR1R163C knock-in mice that increased passive SR Ca2+ leak causes an enlarged basal influx of sarcolemmal Ca 2+ that results in chronically elevated myoplasmic free Ca 2+ concentration ([Ca2+]i) at rest. We discovered that Gd+3 and GsMTx-4 were more effective than BTP2 or expression of the dominant-negative Orai1E190Q in reducing both Ca2+ entry and [Ca2+]i, implicating a non-STIM1/ Orai1 SOCE pathway in resetting resting [Ca2+] i. Indeed, two nonselective cationic channels, TRPC3 and TRPC6, are overexpressed, and [Na]i is chronically elevated in MH-RyR1 R163C muscle cells. [Ca2+]i and [Na +]i are persistently elevated in vivo and further increased by halothane in MH-RyR1R163C/WT muscle. These increases are markedly attenuated by local perfusion of Gd+3 or GsMTx-4 and completely suppressed by dantrolene. These results contribute a new paradigm for understanding MH pathophysiology by demonstrating that nonselective sarcolemmal cation channel activity plays a critical role in causing myoplasmic Ca 2+ and Na+ overload both at rest and during the MH crisis.
Original language | English (US) |
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Pages (from-to) | 991-1000 |
Number of pages | 10 |
Journal | FASEB Journal |
Volume | 27 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2013 |
Keywords
- Dantrolene
- Skeletal muscle
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Genetics
- Molecular Biology